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Journal of NeuroVirology

, Volume 24, Issue 6, pp 679–694 | Cite as

Peripheral and cerebrospinal fluid immune activation and inflammation in chronically HIV-infected patients before and after virally suppressive combination antiretroviral therapy (cART)

  • E. Merlini
  • F. Iannuzzi
  • A. Calcagno
  • F. Bai
  • M. Trunfio
  • A. d’Arminio Monforte
  • S. Bonora
  • Giulia Marchetti
Article
  • 68 Downloads

Abstract

Cerebrospinal fluid (CSF)/plasma HIV-RNA ratio has been associated with residual neurocognitive impairment on cART, leading us to hypothesize a specific peripheral and/or CSF immune feature in patients with high CSF/plasma ratio (≥ 1). In patients with diverse pre-cART CSF/plasma ratio (61/70 with CSF/plasma ratio < 1, L-CSF, 9/70 with CSF/plasma ratio ≥ 1, H-CSF), we investigated the effects of 12 months of effective cART on peripheral and CSF inflammatory markers, on T cell activation/maturation and HIV/CMV-specific intracellular cytokine pattern. We also studied the possible clinical association between peripheral/CSF pro-inflammatory milieu and neurocognitive screening tests (MMSE, FAB, IHDS). Prior to cART, the two groups were comparable for peripheral and CSF inflammation, T cell activation/proliferation and maturation, and HIV/CMV-specific response. Upon cART initiation, both H-CSF and L-CSF featured a significant reduction in plasma TNF-α and circulating CD8 activation, with a redistribution of memory/naïve T cell subsets in L-CSF alone. In the CSF compartment, cART seemed able to reduce pro-inflammatory cytokine/chemokine levels in both H-CSF and L-CSF patients. Interestingly, despite a reduction in the pro-inflammatory milieu, no changes were shown in neurocognitive screening tests in both patients’ groups. We hereby show that 12-month cART is able to reduce intratechal and peripheral pro-inflammatory burden; a longer cART exposure and a more comprehensive neuropsychological evaluation might be necessary to gain a broader insight into the possible effects on neurocognitive performance.

Keywords

CSF/plasma HIV-RNA ratio HIV-associated neurocognitive disorders Peripheral immune activation CSF inflammatory markers 

Notes

Acknowledgements

We thank all of the patients who participated in the study and the staff of the Clinic of Infectious Diseases and Tropical Medicine at “ASST Santi Paolo e Carlo”, Milan and of Amedeo di Savoia Hospital, Turin who cared for the patients. Presented in part at 8th IAS Conference on HIV Pathogenesis, Treatment and Prevention, Vancouver, B.C., Canada (19-22 July2015). Oral Poster #TUPDA0101.

Funding

This study was supported by Gilead Fellowship 2012 grant number F61bd8c044 to G.M.

Compliance with ethical standards

Ethics approval and consent to participate

The ethics committee of the Clinic of Infectious Diseases, University of Milan-ASST Santi Paolo e Carlo, Milan and of Amedeo di Savoia Hospital, Turin (Italy) approved this study. All subjects gave written informed consent in accordance with the Declaration of Helsinki.

Conflict of interest

E.M., F.I., A.C., F.B., M.T., A.D.M., and S.B. declare that they have no conflict of interests. G.M. received research grant by Gilead.

References

  1. Abdulle S, Mellgren A, Brew BJ, Cinque P, Hagberg L, Price RW, Rosengren L, Gisslen M (2007) CSF neurofilament protein (NFL) -- a marker of active HIV-related neurodegeneration. J Neurol 254:1026–1032CrossRefGoogle Scholar
  2. Anthony IC, Bell JE (2008) The neuropathology of HIV/AIDS. Int Rev Psychiatry 20:15–24CrossRefPubMedGoogle Scholar
  3. Anthony IC, Ramage SN, Carnie FW, Simmonds P, Bell JE (2005) Influence of HAART on HIV-related CNS disease and neuroinflammation. J Neuropathol Exp Neurol 64:529–536CrossRefPubMedGoogle Scholar
  4. Bai F, Iannuzzi F, Merlini E, Borghi L, Tincati C, Trunfio M, Bini T, Monforte AD, Marchetti G (2017) Clinical and viro-immunological correlates of HIV associated neurocognitive disorders (HAND) in a cohort of antiretroviral-naive HIV-infected patients. Aids 31:311–314CrossRefPubMedGoogle Scholar
  5. Becker JT, Kingsley L, Mullen J, Cohen B, Martin E, Miller EN, Ragin A, Sacktor N, Selnes OA, Visscher BR (2009) Vascular risk factors, HIV serostatus, and cognitive dysfunction in gay and bisexual men. Neurology 73:1292–1299CrossRefPubMedPubMedCentralGoogle Scholar
  6. Betts MR, Nason MC, West SM, De Rosa SC, Migueles SA, Abraham J, Lederman MM, Benito JM, Goepfert PA, Connors M, Roederer M, Koup RA (2006) HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells. Blood 107:4781–4789CrossRefPubMedPubMedCentralGoogle Scholar
  7. Bossi P, Dupin N, Coutellier A, Bricaire F, Lubetzki C, Katlama C, Calvez V (1998) The level of human immunodeficiency virus (HIV) type 1 RNA in cerebrospinal fluid as a marker of HIV encephalitis. Clin Infect Dis 26:1072–1073CrossRefPubMedGoogle Scholar
  8. Brown LA, Scarola J, Smith AJ, Sanberg PR, Tan J, Giunta B (2014) The role of tau protein in HIV-associated neurocognitive disorders. Mol Neurodegener 9:40CrossRefPubMedPubMedCentralGoogle Scholar
  9. Calcagno A, Romito A, Atzori C, Ghisetti V, Cardellino C, Audagnotto S, Scarvaglieri E, Lipani F, Imperiale D, Di Perri G, Bonora S (2017) Blood brain barrier impairment in HIV-positive naive and effectively treated patients: immune activation versus Astrocytosis. J NeuroImmune Pharmacol 12:187–193CrossRefPubMedGoogle Scholar
  10. Caragounis EC, Gisslen M, Lindh M, Nordborg C, Westergren S, Hagberg L, Svennerholm B (2008) Comparison of HIV-1 pol and env sequences of blood, CSF, brain and spleen isolates collected ante-mortem and post-mortem. Acta Neurol Scand 117:108–116PubMedGoogle Scholar
  11. Cassol E, Misra V, Morgello S, Gabuzda D (2013) Applications and limitations of inflammatory biomarkers for studies on neurocognitive impairment in HIV infection. J NeuroImmune Pharmacol 8:1087–1097CrossRefPubMedPubMedCentralGoogle Scholar
  12. Childs EA, Lyles RH, Selnes OA, Chen B, Miller EN, Cohen BA, Becker JT, Mellors J, McArthur JC (1999) Plasma viral load and CD4 lymphocytes predict HIV-associated dementia and sensory neuropathy. Neurology 52:607–613CrossRefPubMedGoogle Scholar
  13. de Souza EM, Buoniconti CS, Valim FC, Moura AS (2016) Risk factors for neurocognitive impairment in HIV-infected patients and comparison of different screening tools. Dement Neuropsychol 10:42–46CrossRefPubMedPubMedCentralGoogle Scholar
  14. Dentone C, Fenoglio D, Schenone E, Cenderello G, Prinapori R, Signori A, Parodi A, Kalli F, Battaglia F, Feasi M, Bruzzone B, Viscoli C, Filaci G, Di Biagio A (2015) Increased CD38 expression on T lymphocytes as a marker of HIV dissemination into the central nervous system. HIV Clin Trials 16:190–196CrossRefPubMedGoogle Scholar
  15. Dubois B, Slachevsky A, Litvan I, Pillon B (2000) The FAB: a frontal assessment battery at bedside. Neurology 55:1621–1626CrossRefGoogle Scholar
  16. Dunfee R, Thomas ER, Gorry PR, Wang J, Ancuta P, Gabuzda D (2006) Mechanisms of HIV-1 neurotropism. Curr HIV Res 4:267–278CrossRefPubMedGoogle Scholar
  17. Eden A, Price RW, Spudich S, Fuchs D, Hagberg L, Gisslen M (2007) Immune activation of the central nervous system is still present after >4 years of effective highly active antiretroviral therapy. J Infect Dis 196:1779–1783CrossRefPubMedGoogle Scholar
  18. Eden A, Marcotte TD, Heaton RK, Nilsson S, Zetterberg H, Fuchs D, Franklin D, Price RW, Grant I, Letendre SL, Gisslen M (2016) Increased intrathecal immune activation in virally suppressed HIV-1 infected patients with neurocognitive impairment. PLoS One 11:e0157160CrossRefPubMedPubMedCentralGoogle Scholar
  19. Ellis RJ, Moore DJ, Childers ME, Letendre S, McCutchan JA, Wolfson T, Spector SA, Hsia K, Heaton RK, Grant I (2002) Progression to neuropsychological impairment in human immunodeficiency virus infection predicted by elevated cerebrospinal fluid levels of human immunodeficiency virus RNA. Arch Neurol 59:923–928CrossRefPubMedGoogle Scholar
  20. Foley J, Ettenhofer M, Wright MJ, Siddiqi I, Choi M, Thames AD, Mason K, Castellon S, Hinkin CH (2010) Neurocognitive functioning in HIV-1 infection: effects of cerebrovascular risk factors and age. Clin Neuropsychol 24:265–285CrossRefPubMedPubMedCentralGoogle Scholar
  21. Gouse H, Casson-Crook M, Decloedt EH, Joska JA, Thomas KGF (2017) Adding a brief self-report cognitive tool to the IHDS improves effectiveness of identifying patients with HIV-associated dementia in South Africa. J Neuro-Oncol 23:686–695Google Scholar
  22. Grauer OM, Reichelt D, Gruneberg U, Lohmann H, Schneider-Hohendorf T, Schulte-Mecklenbeck A, Gross CC, Meuth SG, Wiendl H, Husstedt IW (2015) Neurocognitive decline in HIV patients is associated with ongoing T-cell activation in the cerebrospinal fluid. Ann Clin Transl Neurol 2:906–919CrossRefPubMedPubMedCentralGoogle Scholar
  23. Green DA, Masliah E, Vinters HV, Beizai P, Moore DJ, Achim CL (2005) Brain deposition of beta-amyloid is a common pathologic feature in HIV positive patients. Aids 19:407–411CrossRefPubMedGoogle Scholar
  24. Haddow LJ, Floyd S, Copas A, Gilson RJ (2013) A systematic review of the screening accuracy of the HIV dementia scale and international HIV dementia scale. PLoS One 8:e61826CrossRefPubMedPubMedCentralGoogle Scholar
  25. Haddow LJ, Laverick R, Daskalopoulou M, McDonnell J, Lampe FC, Gilson R, Speakman A, Antinori A, Balestra P, Bruun T, Gerstoft J, Nielsen L, Vassilenko A, Collins S, Rodger AJ (2018) Multicenter European prevalence study of neurocognitive impairment and associated factors in HIV positive patients. AIDS Behav 22(5):1573–1583CrossRefPubMedCentralGoogle Scholar
  26. Harari A, Petitpierre S, Vallelian F, Pantaleo G (2004a) Skewed representation of functionally distinct populations of virus-specific CD4 T cells in HIV-1-infected subjects with progressive disease: changes after antiretroviral therapy. Blood 103:966–972CrossRefPubMedGoogle Scholar
  27. Harari A, Vallelian F, Pantaleo G (2004b) Phenotypic heterogeneity of antigen-specific CD4 T cells under different conditions of antigen persistence and antigen load. Eur J Immunol 34:3525–3533CrossRefPubMedGoogle Scholar
  28. Harrington PR, Schnell G, Letendre SL, Ritola K, Robertson K, Hall C, Burch CL, Jabara CB, Moore DT, Ellis RJ, Price RW, Swanstrom R (2009) Cross-sectional characterization of HIV-1 env compartmentalization in cerebrospinal fluid over the full disease course. Aids 23:907–915CrossRefPubMedPubMedCentralGoogle Scholar
  29. Heaton RK, Clifford DB, Franklin DR Jr, Woods SP, Ake C, Vaida F, Ellis RJ, Letendre SL, Marcotte TD, Atkinson JH, Rivera-Mindt M, Vigil OR, Taylor MJ, Collier AC, Marra CM, Gelman BB, McArthur JC, Morgello S, Simpson DM, McCutchan JA, Abramson I, Gamst A, Fennema-Notestine C, Jernigan TL, Wong J, Grant I (2010) HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER study. Neurology 75:2087–2096CrossRefPubMedPubMedCentralGoogle Scholar
  30. Heaton RK, Franklin DR, Ellis RJ, McCutchan JA, Letendre SL, Leblanc S, Corkran SH, Duarte NA, Clifford DB, Woods SP, Collier AC, Marra CM, Morgello S, Mindt MR, Taylor MJ, Marcotte TD, Atkinson JH, Wolfson T, Gelman BB, McArthur JC, Simpson DM, Abramson I, Gamst A, Fennema-Notestine C, Jernigan TL, Wong J, Grant I, Group C, Group H (2011) HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors. J Neuro-Oncol 17:3–16Google Scholar
  31. Hong S, Banks WA (2015) Role of the immune system in HIV-associated neuroinflammation and neurocognitive implications. Brain Behav Immun 45:1–12CrossRefPubMedGoogle Scholar
  32. Hu X, Zhou Y, Long J, Feng Q, Wang R, Su L, Zhao T, Wei B (2012) Diagnostic accuracy of the international HIV dementia scale and HIV dementia scale: a meta-analysis. Exp Ther Med 4:665–668CrossRefPubMedPubMedCentralGoogle Scholar
  33. Hurtado-Pomares M, Carmen Terol-Cantero M, Sanchez-Perez A, Peral-Gomez P, Valera-Gran D, Navarrete-Munoz EM (2018) The frontal assessment battery in clinical practice: a systematic review. Int J Geriatr Psychiatry 33(2):237–251CrossRefPubMedGoogle Scholar
  34. Letendre S (2011) Central nervous system complications in HIV disease: HIV-associated neurocognitive disorder. Top Antivir Med 19:137–142PubMedGoogle Scholar
  35. Manji H, Jager HR, Winston A (2013) HIV, dementia and antiretroviral drugs: 30 years of an epidemic. J Neurol Neurosurg Psychiatry 84:1126–1137CrossRefPubMedGoogle Scholar
  36. Marin-Webb V, Jessen H, Kopp U, Jessen AB, Hahn K (2016) Validation of the international HIV dementia scale as a screening tool for HIV-associated neurocognitive disorders in a German-speaking HIV outpatient clinic. PLoS One 11:e0168225CrossRefPubMedPubMedCentralGoogle Scholar
  37. Marra CM, Zhao Y, Clifford DB, Letendre S, Evans S, Henry K, Ellis RJ, Rodriguez B, Coombs RW, Schifitto G, McArthur JC, Robertson K, Team ACTGS (2009) Impact of combination antiretroviral therapy on cerebrospinal fluid HIV RNA and neurocognitive performance. AIDS 23:1359–1366CrossRefPubMedPubMedCentralGoogle Scholar
  38. McGuire JL, Gill AJ, Douglas SD, Kolson DL (2015) Central and peripheral markers of neurodegeneration and monocyte activation in HIV-associated neurocognitive disorders. J Neuro-Oncol 21:439–448Google Scholar
  39. Mellgren A, Price RW, Hagberg L, Rosengren L, Brew BJ, Gisslen M (2007) Antiretroviral treatment reduces increased CSF neurofilament protein (NFL) in HIV-1 infection. Neurology 69:1536–1541CrossRefGoogle Scholar
  40. Milanini B, Ciccarelli N, Fabbiani M, Baldonero E, Limiti S, Gagliardini R, Borghetti A, D'Avino A, Mondi A, Colafigli M, Cauda R, Di Giambenedetto S (2016) Neuropsychological screening tools in Italian HIV+ patients: a comparison of Montreal cognitive assessment (MoCA) and mini mental state examination (MMSE). Clin Neuropsychol 30:1457–1468CrossRefPubMedGoogle Scholar
  41. Motta I, Allice T, Romito A, Ferrara M, Ecclesia S, Imperiale D, Ghisetti V, Di Perri G, Bonora S, Calcagno A (2017) Cerebrospinal fluid viral load and neopterin in HIV-positive patients with undetectable viraemia. Antivir Ther 22:539–543CrossRefPubMedGoogle Scholar
  42. Nightingale S, Winston A, Letendre S, Michael BD, McArthur JC, Khoo S, Solomon T (2014) Controversies in HIV-associated neurocognitive disorders. Lancet Neurol 13:1139–1151CrossRefPubMedPubMedCentralGoogle Scholar
  43. Peluso MJ, Meyerhoff DJ, Price RW, Peterson J, Lee E, Young AC, Walter R, Fuchs D, Brew BJ, Cinque P, Robertson K, Hagberg L, Zetterberg H, Gisslen M, Spudich S (2013) Cerebrospinal fluid and neuroimaging biomarker abnormalities suggest early neurological injury in a subset of individuals during primary HIV infection. J Infect Dis 207:1703–1712CrossRefPubMedPubMedCentralGoogle Scholar
  44. Rahimy E, Li FY, Hagberg L, Fuchs D, Robertson K, Meyerhoff DJ, Zetterberg H, Price RW, Gisslen M, Spudich S (2017) Blood-brain barrier disruption is initiated during primary HIV infection and not rapidly altered by antiretroviral therapy. J Infect Dis 215:1132–1140CrossRefPubMedPubMedCentralGoogle Scholar
  45. Rawson TM, Dubb S, Pozniak A, Kelleher WP, Mandalia S, Gazzard B, Barber TJ (2015) Assessing the role of peripheral CD8 T cells in neurocognitive impairment in HIV-infected men who have sex with men: data from the MSM Neurocog study. Int J STD AIDS 26:128–132CrossRefPubMedGoogle Scholar
  46. Ryan LA, Zheng J, Brester M, Bohac D, Hahn F, Anderson J, Ratanasuwan W, Gendelman HE, Swindells S (2001) Plasma levels of soluble CD14 and tumor necrosis factor-alpha type II receptor correlate with cognitive dysfunction during human immunodeficiency virus type 1 infection. J Infect Dis 184:699–706CrossRefPubMedGoogle Scholar
  47. Sacktor NC, Wong M, Nakasujja N, Skolasky RL, Selnes OA, Musisi S, Robertson K, McArthur JC, Ronald A, Katabira E (2005) The international HIV dementia scale: a new rapid screening test for HIV dementia. Aids 19:1367–1374PubMedGoogle Scholar
  48. Sanchez AB, Kaul M (2017) Neuronal stress and injury caused by HIV-1, cART and drug abuse: converging contributions to HAND. Brain Sci 7(3):E25CrossRefPubMedCentralGoogle Scholar
  49. Schnell G, Price RW, Swanstrom R, Spudich S (2010) Compartmentalization and clonal amplification of HIV-1 variants in the cerebrospinal fluid during primary infection. J Virol 84:2395–2407CrossRefGoogle Scholar
  50. Schrier RD, Hong S, Crescini M, Ellis R, Perez-Santiago J, Spina C, Letendre S (2015) Cerebrospinal fluid (CSF) CD8+ T-cells that express interferon-gamma contribute to HIV associated neurocognitive disorders (HAND). PLoS One 10:e0116526CrossRefPubMedPubMedCentralGoogle Scholar
  51. Sevigny JJ, Albert SM, McDermott MP, McArthur JC, Sacktor N, Conant K, Schifitto G, Selnes OA, Stern Y, McClernon DR, Palumbo D, Kieburtz K, Riggs G, Cohen B, Epstein LG, Marder K (2004) Evaluation of HIV RNA and markers of immune activation as predictors of HIV-associated dementia. Neurology 63:2084–2090CrossRefPubMedGoogle Scholar
  52. Sinclair E, Ronquillo R, Lollo N, Deeks SG, Hunt P, Yiannoutsos CT, Spudich S, Price RW (2008) Antiretroviral treatment effect on immune activation reduces cerebrospinal fluid HIV-1 infection. J Acquir Immune Defic Syndr 47:544–552CrossRefPubMedPubMedCentralGoogle Scholar
  53. Soulie C, Fourati S, Lambert-Niclot S, Tubiana R, Canestri A, Girard PM, Katlama C, Morand-Joubert L, Calvez V, Marcelin AG (2010) HIV genetic diversity between plasma and cerebrospinal fluid in patients with HIV encephalitis. Aids 24:2412–2414PubMedGoogle Scholar
  54. Spudich SS (2016) Immune activation in the central nervous system throughout the course of HIV infection. Curr Opin HIV AIDS 11:226–233CrossRefPubMedPubMedCentralGoogle Scholar
  55. Spudich S, Gonzalez-Scarano F (2012) HIV-1-related central nervous system disease: current issues in pathogenesis, diagnosis, and treatment. Cold Spring Harb Perspect Med 2:a007120CrossRefPubMedPubMedCentralGoogle Scholar
  56. Spudich SS, Nilsson AC, Lollo ND, Liegler TJ, Petropoulos CJ, Deeks SG, Paxinos EE, Price RW (2005) Cerebrospinal fluid HIV infection and pleocytosis: relation to systemic infection and antiretroviral treatment. BMC Infect Dis 5:98CrossRefPubMedPubMedCentralGoogle Scholar
  57. Spudich S, Gisslen M, Hagberg L, Lee E, Liegler T, Brew B, Fuchs D, Tambussi G, Cinque P, Hecht FM, Price RW (2011) Central nervous system immune activation characterizes primary human immunodeficiency virus 1 infection even in participants with minimal cerebrospinal fluid viral burden. J Infect Dis 204:753–760CrossRefPubMedPubMedCentralGoogle Scholar
  58. Tan IL, McArthur JC (2012) HIV-associated neurological disorders: a guide to pharmacotherapy. CNS Drugs 26:123–134CrossRefPubMedPubMedCentralGoogle Scholar
  59. Trunfio M, Vai D, Montrucchio C, Alcantarini C, Livelli A, Tettoni MC, Orofino G, Audagnotto S, Imperiale D, Bonora S, Di Perri G, Calcagno A (2018) Diagnostic accuracy of new and old cognitive screening tools for HIV-associated neurocognitive disorders. HIV Med.  https://doi.org/10.1111/hiv.12622 CrossRefGoogle Scholar
  60. Valcour V, Chalermchai T, Sailasuta N, Marovich M, Lerdlum S, Suttichom D, Suwanwela NC, Jagodzinski L, Michael N, Spudich S, van Griensven F, de Souza M, Kim J, Ananworanich J (2012) Central nervous system viral invasion and inflammation during acute HIV infection. J Infect Dis 206:275–282CrossRefPubMedPubMedCentralGoogle Scholar
  61. Vandergeeten C, Fromentin R, Merlini E, Lawani MB, DaFonseca S, Bakeman W, McNulty A, Ramgopal M, Michael N, Kim JH, Ananworanich J, Chomont N (2014) Cross-clade ultrasensitive PCR-based assays to measure HIV persistence in large-cohort studies. J Virol 88:12385–12396CrossRefPubMedPubMedCentralGoogle Scholar
  62. Vassallo M, Durant J, Lebrun-Frenay C, Fabre R, Ticchioni M, Andersen S, DeSalvador F, Harvey-Langton A, Dunais B, Cohen-Codar I, Montagne N, Cua E, Fredouille-Heripret L, Laffon M, Cottalorda J, Dellamonica P, Pradier C (2015) Virologically suppressed patients with asymptomatic and symptomatic HIV-associated neurocognitive disorders do not display the same pattern of immune activation. HIV Med 16:431–440CrossRefPubMedGoogle Scholar
  63. Vitiello B, Goodkin K, Ashtana D, Shapshak P, Atkinson JH, Heseltine PN, Eaton E, Heaton R, Lyman WD (2007) HIV-1 RNA concentration and cognitive performance in a cohort of HIV-positive people. Aids 21:1415–1422CrossRefPubMedGoogle Scholar
  64. Wright EJ, Grund B, Robertson K, Brew BJ, Roediger M, Bain MP, Drummond F, Vjecha MJ, Hoy J, Miller C, Penalva de Oliveira AC, Pumpradit W, Shlay JC, El-Sadr W, Price RW (2010) Cardiovascular risk factors associated with lower baseline cognitive performance in HIV-positive persons. Neurology 75:864–873CrossRefPubMedPubMedCentralGoogle Scholar
  65. Yilmaz A, Price RW, Spudich S, Fuchs D, Hagberg L, Gisslen M (2008) Persistent intrathecal immune activation in HIV-1-infected individuals on antiretroviral therapy. J Acquir Immune Defic Syndr 47:168–173CrossRefPubMedPubMedCentralGoogle Scholar
  66. Yilmaz A, Blennow K, Hagberg L, Nilsson S, Price RW, Schouten J, Spudich S, Underwood J, Zetterberg H, Gisslen M (2017) Neurofilament light chain protein as a marker of neuronal injury: review of its use in HIV-1 infection and reference values for HIV-negative controls. Expert Rev Mol Diagn 17(8):761–770CrossRefPubMedGoogle Scholar
  67. Zayyad Z, Spudich S (2015) Neuropathogenesis of HIV: from initial neuroinvasion to HIV-associated neurocognitive disorder (HAND). Curr HIV/AIDS Rep 12:16–24CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Journal of NeuroVirology, Inc. 2018

Authors and Affiliations

  • E. Merlini
    • 1
  • F. Iannuzzi
    • 1
  • A. Calcagno
    • 2
  • F. Bai
    • 1
  • M. Trunfio
    • 2
  • A. d’Arminio Monforte
    • 1
  • S. Bonora
    • 2
  • Giulia Marchetti
    • 1
  1. 1.Department of Health Sciences, Clinic of Infectious Diseases, ASST Santi Paolo e CarloUniversity of MilanMilanItaly
  2. 2.Unit of Infectious Diseases, Department of Medical SciencesUniversity of TurinTurinItaly

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